Despite the currently available effective prophylactic vaccines, human papilloma virus infections remain the most common cause of venereal disease. Human papilloma virus-associated diseases are particularly prevalent in medically underserved segments of the population. Despite decades of research, there are no strategies that can limit the spread of human papilloma viruses. The productive viral life cycle of these viruses has been studied extensively, but research has almost exclusively focused on the contributions of viral and cellular proteins and protein-coding mRNAs. However, most of the cellular transcriptome does not encode proteins. Some non-coding RNAs likely represent functionally irrelevant transcriptional noise but several classes of non-coding RNAs serve important regulatory functions. Long non-coding RNAs have only recently emerged as critical modulators of many cellular regulatory circuits. Human papilloma viruses replicate their genomes to high copy numbers and generate progeny virus in terminally differentiated epithelial cells. We showed that expression of the long non-coding RNA DINO increases during epithelial differentiation and that ectopic expression of the long noncoding RNA DINO in a patient-derived, human papillomavirus episome- containing cell line causes an increase in viral genomes. This proposal addresses the hypothesis that DINO plays a previously unanticipated role in regulating the differentiation-dependent life cycle of human papillomaviruses. We will deploy a combination of biochemical, cell and molecular biology approaches to define the biological activities of DINO in human papillomavirus genome replication in dividing and differentiated viral episome-containing, patient-derived cell lines. The results from our studies will yield novel molecular insights into the differentiation-dependent life cycle of human papillomaviruses.